WO2002053187A2 - Methodes et compositions transdermiques pour le soulagement de la douleur - Google Patents

Methodes et compositions transdermiques pour le soulagement de la douleur

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Publication number
WO2002053187A2
WO2002053187A2 PCT/US2002/000019 US0200019W WO02053187A2 WO 2002053187 A2 WO2002053187 A2 WO 2002053187A2 US 0200019 W US0200019 W US 0200019W WO 02053187 A2 WO02053187 A2 WO 02053187A2
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WO
WIPO (PCT)
Prior art keywords
transdermal composition
compound
amine containing
transdermal
containing compound
Prior art date
Application number
PCT/US2002/000019
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English (en)
Other versions
WO2002053187A3 (fr
Inventor
Robert Murdock
C. Donald Williams
Original Assignee
Pharmaceuticals Applications Associates, Llc
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Filing date
Publication date
Application filed by Pharmaceuticals Applications Associates, Llc filed Critical Pharmaceuticals Applications Associates, Llc
Priority to AU2002234192A priority Critical patent/AU2002234192A1/en
Publication of WO2002053187A2 publication Critical patent/WO2002053187A2/fr
Publication of WO2002053187A3 publication Critical patent/WO2002053187A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention is directed to methods and compositions for transdermal administration.
  • the present invention is directed to methods and compositions for the transdermal administration of an amine containing compound having biphasic solubility and/or an agent which enhances the activity of the amine containing compound having biphasic solubility, e.g. , a muscle relaxant, to relieve pain.
  • somatic sensory nerves causes a somatic sensory loss.
  • damage can be caused by a variety of means including trauma, diseases such as diabetes, he ⁇ es zoster and late-stage cancer, chemotherapy, or by a chemical injury.
  • neural pain circuits rewire themselves, both anatomically and biochemically, after nerve injury.
  • negative symptoms such as numbness are joined by positive sensations, involving a sort of false sensation of pain.
  • the experience can range from mild dysesthesia to excruciating pain, rendering some patients unable to work, walk or do other daily activities.
  • oral administration involves a time delay as the analgesic is absorbed via the digestive system before entering the bloodstream.
  • dosages which are appropriate for oral administration, upon being distributed more or less uniformly throughout the body are undesirably low in a particular area, e.g., tissue, to achieve desired results.
  • Oral or injection administration may result in too slow or too rapid increase in blood plasma levels, e.g., may involve an undesirably long time delay as the analgesic is absorbed by the digestive system before entering the bloodstream, or may result in a "spike" in blood plasma levels followed by an undesirably low level, where a more constant level would be preferable.
  • Some analgesics are particularly prone to cause or contribute to kidney or liver damage when administered orally.
  • the present invention provides a transdermal composition for the treatment of pain in a subject, particularly a human subject.
  • the transdermal composition for the treatment of pain in a subject includes an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound, e.g. , a lecithin organogel carrier.
  • the transdermal composition further includes an agent which enhances the activity of the amine containing compound having biphasic solubility, e.g., a muscle relaxant, such as guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof.
  • a muscle relaxant such as guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof.
  • the agent which enhances the activity of the amine containing compound having biphasic solubility e.g., the muscle relaxant, also has a biphasic solubility.
  • the amine containing compound having biphasic solubility is an antidepressant compound, such as a tricyclic antidepressant compound, e.g. , doxepin or trimipramine.
  • the amine containing compound having biphasic solubility is a sodium channel blocker, a calcium channel blocker, an anti-epileptic compound, or an anti-convulsant compound.
  • transdermal composition which includes an amine-containing compound as described herein and an anti-inflammatory compound, such as a nonsteroidal anti-inflammatory compound, e.g., celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx ® , and combinations thereof.
  • an anti-inflammatory compound such as a nonsteroidal anti-inflammatory compound, e.g., celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx ® , and combinations thereof.
  • an agent which enhances the activity of the amine containing compound e.g., a muscle relaxant such as guaifenesin.
  • the invention features a transdermal composition for the treatment of pain in a subject including an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject; a muscle relaxant in an amount effective to enhance the activity of the amine containing compound having biphasic solubility; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound having biphasic solubility and the muscle relaxant.
  • the invention features a transdermal composition for the treatment of pain in a subject including doxepin in an amount effective to treat pain in a subject; guaifenesin in an amount effective to enhance the activity of doxepin; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the doxepin and the guaifenesin.
  • transdermal composition including an amine containing compound having biphasic solubility in an amount effective to treat pain in the subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound to thereby treat pain in the subject.
  • the transdermal composition is applied to the skin of the subject.
  • Another aspect of the invention features a method for selecting a compound suitable for treating pain in a subject.
  • the method includes transdermally administering an amine containing compound having biphasic solubility to a subject; and determining whether pain is treated in the subject to thereby select a compound suitable for treating pain in a subject.
  • the method can further include modeling the compound using a computer equipped with a three-dimensional chemical structure modeling program; and determining whether the three-dimensional chemical structure of the compound possesses sufficient characteristics to be useful as a sodium channel blocker or a calcium channel blocker, thereby selecting a compound suitable for treating pain in a subject.
  • the invention features a transdermal composition suitable for transdermal delivery, which includes a therapeutically effective amount of a pharmaceutical compound (e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal delivery of the pharmaceutical compound, e.g., a lecithin organogel carrier.
  • a pharmaceutical compound e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence
  • a pharmaceutically acceptable carrier suitable for transdermal delivery of the pharmaceutical compound, e.g.,
  • the invention features a transdermal composition for treatment of pain in a subject which includes a compound capable of blocking afferent neuron transmission in an amount effective to block afferent neuron transmission in a subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the compound.
  • the present invention features transdermal compositions comprising lamotrigine and doxepin; topiramate and chlorzoxazone; topiramate and guaifenesin; topiramate and doxepin; topiramate and naproxen; doxepin and chlorzoxazone; lamotrigine and guaifenesin; lamotrigine, doxepin, and guaifenesin; or lamotrigine, doxepin, and chlorzoxazone.
  • Figure 1 is an evaluation form used in evaluating an embodiment of the present invention.
  • Figure 2 is a table depicting the results from clinical experiments using compositions of the invention. Detailed Description Of The Invention
  • the present invention provides a transdermal composition suitable for treatment of pain in a subject.
  • the transdermal composition includes an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound having biphasic solubility.
  • the term "subject” includes a mammal, such as a human, a horse, a pig, a cow, a mouse, a rat, a rabbit, or a goat. In preferred embodiment, the subject is a human.
  • the term "pain” is art recognized and includes a bodily sensation elicited by noxious chemical, mechanical, or thermal stimuli, in a subject, e.g., a mammal such as a human.
  • the term “pain” includes chronic pain, such as lower back pain; pain due to arthritis, e.g., osteoarthritis; joint pain, e.g., knee pain or carpal tunnel syndrome; myofascial pain, and neuropathic pain.
  • the term "pain” further includes acute pain, such as pain associated with muscle strains and sprains; tooth pain; headaches; pain associated with surgery; or pain associated with various forms of tissue injury, e.g., inflammation, infection, and ischemia.
  • amine containing compound having biphasic solubility includes compounds having at least one amine moiety and having sufficient lipid solubility (e.g., solubility in polar solvents such as ethanol, ethoxy diglycerol, ethoxydiglycol, chloroform, benzene, and the like) such that the compound passes through the stratum corneum, and has sufficient aqueous solubility to be active in the aqueous environment of the dermis and the underlying tissue.
  • lipid solubility e.g., solubility in polar solvents such as ethanol, ethoxy diglycerol, ethoxydiglycol, chloroform, benzene, and the like
  • Transdermal compositions of the present invention include an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject.
  • amount effective to treat pain in a subject and “effective amount” are used interchangeably herein and include an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to treat pain in a subject.
  • An effective amount of an amine containing compound or a pharmaceutical compound as defined herein may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the amine containing compound or pharmaceutical compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • transdermal compositions of the invention can further include an agent which enhances the activity of the amine containing compound having biphasic solubility.
  • an "agent which enhances the activity of the amine containing compound having biphasic solubility” includes an agent which enhances the pharmacological activity of the amine containing compound having biphasic solubility (e.g., the ability of the amine containing compound to treat pain), or enhances the transdermal delivery of the amine containing compound having biphasic solubility (e.g., the ability of the amine containing compound to cross the stratum corneum), or enhances both the pharmacological activity and the transdermal delivery of the amine containing compound.
  • agents which enhance the activity of the amine containing compound having biphasic solubility include muscle relaxants, described in further detail below.
  • transdermal composition includes compositions capable of passing through the stratum corneum of a subject.
  • transdermal further includes compositions capable of passing through the epidermis of a subject, compositions capable of passing through the dermis of a subject, and compositions capable of passing through the hypodermis of a subject.
  • transdermal includes compositions capable of passing through the skin of a subject and reaching the underlying tissues and organs.
  • transdermal delivery includes delivery of, for example, a compound through the stratum corneum of a subject.
  • transdermal delivery further includes delivery of, for example, a compound through the epidermis of a subject, delivery of, for example, a compound through the dermis of a subject, and delivery of, for example, a compound through the hypodermis of a subject.
  • transdermal delivery includes delivery of, for example, a compound through the skin of a subject to the underlying tissues and organs.
  • the present invention further features a transdermal composition for treatment of pain in a subject which includes a compound capable of blocking afferent neuron transmission in an amount effective to block afferent neuron transmission in a subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the compound.
  • the term "compound capable of blocking afferent neuron transmission” includes a compound which is capable of blocking the ability of an afferent neuron, i.e., a sensory neuron, to carry an impulse toward the central nervous system.
  • Amine Containing Compounds Having Biphasic Solubility include antidepressant compounds, antiepileptic compounds, anticonvulsant compounds, sodium channel blockers and calcium channel blockers.
  • antidepressant compounds includes compounds capable of alleviating the symptoms of depression.
  • antidepressant compounds include all tricyclic antidepressants (e.g., amitriptyline, dothiepin, or lofepramine), bupropion (sold under the trade name Wellbutrin), reboxetine (sold under the trade name Edronax), nefazodone (sold under the trade name Serzone) and trazodone (sold under the trade name Desyrel).
  • Antidepressant compounds are described in, for example, the 1998 SIGMA catalogue and the "The Merck Index", 12t:h Ed., Budavari et al, eds., Merck & Co., Inc., Railway, N.J., 1996, the contents of which are incorporated herein by reference.
  • a transdermal composition of the present invention includes a tricyclic antidepressant compounds.
  • exemplary tricyclic antidepressants include adinazolam, amitriptylinoxide, amoxapine, clomipramine, demexiptiline, dimetacrine, dothiepin, doxepin, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, noxiptilin, pizotyline, propizepine, quinupramine, tianeptine, and trimipramine.
  • a particularly preferred tricyclic antidepressant for use in the compositions of the invention is doxepin.
  • Tricyclic antidepressant compounds are described in, for example, "Guide to Clinical Neurology” by J.P. Mohr et al. (Churchill Livingstone, 1995), the contents of which are incorporated herein by reference.
  • the tricyclic antidepressant compound is selected from the group consisting of doxepin, trimipramine, other tricyclics having biphasic solubility, and combinations thereof.
  • the tricyclic antidepressant When combined with other compounds, such as an agent which enhances the activity of the amine containing compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g., a nonsteroidal anti-inflammatory compound, as discussed below, the tricyclic antidepressant preferably constitutes from about 1 % by weight (% by wt.) to about 30 % by wt. of the total amount of the pharmaceutical, more preferably from about 3 % by wt;.
  • the amine containing compounds having biphasic solubility used in the transdermal compositions of the invention further include antiepileptic compounds.
  • antiepileptic compound includes compounds capable of alleviating the symptoms of epilepsy.
  • Exemplary antiepileptic compounds for use in the compounds of the invention include lamotrigine, felbamate, and carbamazepine.
  • the antiepileptic compound is selected from the group consisting of lamotrigine, felbamate, carbamazepine, and combinations thereof.
  • the antiepileptic compound constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt., and most preferably from about 5 % by wt. to about 15 % by wt.
  • Antiepileptic compounds are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al, eds., Merck & Co., Inc., Rahway, N.J., 1996, and the "Guide to Clinical Neurology” by J.P. Mohr et al. (Churchill Livingstone, 1995) the contents of which are inco ⁇ orated herein by reference.
  • the amine containing compounds having biphasic solubility of the present invention include anticonvulsant compounds.
  • anticonvulsant compound includes compounds capable of alleviating the symptoms of convulsion, i.e., the violent involuntary tetanic contractions of an entire group of muscles.
  • exemplary anticonvulsant compounds which for use in the compositions of the invention include felbamate, lamotrigine and carbamazepine.
  • the anticonvulsant compound is selected from the group consisting of felbamate, lamotrigine, and combinations thereof.
  • the anticonvulsant compound When combined with other compounds, such as an agent which enhances the activity of the amine containing compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g., a nonsteroidal anti-inflammatory compound as discussed below, the anticonvulsant compound constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt., and most preferably from about 5 % by wt. to about 15 % by wt.
  • an agent which enhances the activity of the amine containing compound e.g., a muscle relaxant
  • an anti-inflammatory compound e.g., a nonsteroidal anti-inflammatory compound as discussed below
  • the amine containing compounds having biphasic solubility of the present invention include adrenergic agonist compounds.
  • the adrenergic agonist compound is tizanidine.
  • the adrenergic agonist compound When combined with other compounds, such as a muscle relaxant and/or nonsteroidal anti-inflammatory compound as discussed below, the adrenergic agonist compound constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt., and most preferably from about 5 % by wt. to about 15 % by wt.
  • Adrenergic agonist compounds are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al, eds., Merck & Co., Inc., Rahway, N.J., 1996, and the "Guide to Clinical Neurology” by J.P. Mohr et al. (Churchill Livingstone, 1995) the contents of which are inco ⁇ orated herein by reference.
  • the amine containing compounds having biphasic solubility used in the transdermal compositions of the invention further include sodium channel blockers and calcium channel blockers.
  • sodium channel blockers includes compounds which are capable of blocking the activity of a sodium channel. Examples of sodium channel blockers include topiramate, tetrodoxin, flecainide, disopyramide, and terfenadine.
  • sodium channel blockers are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al, eds., Merck & Co., Inc., Rahway, N. J., 1996, and the "Guide to Clinical Neurology" by J.P.
  • calcium channel blockers includes compounds which are capable of blocking the activity of a calcium channel.
  • Examples of calcium channel blockers include Arylalkylamines, e.g., Bepridil, Clentiazem, Diliazem, Fendiline, Gallopamil, Mibefradil, Prenylamine, Semotiadil, Terodiline, or Nerapamil; Dihydropyridine Derivatives, e.g., Amlodipine, Aranidipine, Barnidipine, Benidipine, Cilnidipine, Bfonidipine, Elgodipine, Felodipine, Isradipine, Lacidpine, Lercanidipine, Manidipine, ⁇ icardipine, ⁇ ifedipine, ⁇ ilvadipine, ⁇ imodipine, ⁇
  • Arylalkylamines e.g., Bepridil, Clentiazem, Diliazem, Fendiline, Gallopam
  • nerves are damaged, for example, by trauma, by diseases such as diabetes, he ⁇ es zoster, or late-stage cancer, or by chemical injury (e.g., as an untoward consequence of agents including the false-nucleoside anti-HIN pharmaceuticals), neural pain circuits rewire themselves, anatomically and/or biochemically.
  • new sodium and calcium channels are formed which are believed to constitute the basis for chronic pain development.
  • chronic regional pain syndromes may develop. Each time one of these sodium and/or calcium channels depolarizes, a nerve impulse originates.
  • the amine moiety of the amine containing compounds having biphasic solubility of the present invention may function similar to a sodium or calcium ion upon entry into the sodium channel of a nerve cell membrane.
  • a non-polar moiety, which is preferably present in the amine containing compound having biphasic solubility of the present invention may interact with the nerve cell membrane, perhaps through Nan der Waals forces. In such cases, it is believed that the presence of the non-polar moiety prevents or inhibits a complete uptake of the amine containing compound having biphasic solubility through the nerve cell membrane. It is believed that one or more these interactions prevent or reduce the amount and/or the rate of depolarization and ion exchange involved in stimulus conduction, thereby decreasing pain sensation.
  • the amount of an amine containing compound having biphasic solubility useful in relieving pain transdermally may be determined by methods known in the art, and typically ranges from about 1 mg to about 300 mg per subject per dose, preferably from about 5 mg to about 100 mg per subject per dose, and more preferably from about 10 mg to about 50 mg per subject per dose, depending on a variety of factors including the particular amine containing compound having biphasic solubility used, whether the area of transdermal application is the site of action, and the intended size of the site of action.
  • the amount of an amine containing compound having biphasic solubility useful in relieving pain transdermally is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg per subject per dose.
  • Transdermal compositions of the present invention may also include a muscle relaxant.
  • muscle relaxant includes compounds which facilitate or enhance the relaxation of muscles (e.g., provide relief from muscle spasm) and, thus, facilitate or enhance the transdermal delivery of the transdermal compositions of the invention.
  • exemplary muscle relaxants include both skeletal muscle relaxants and smooth muscle relaxants such as anticholinergics, antispasmodics, bronchodilators, and vasodilators.
  • Muscle relaxants are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al, eds., Merck & Co., Inc., Rahway, N.J., 1996, pp. THER-1 to THER-28, and the "Guide to Clinical Neurology” by J.P. Mohr et al. (Churchill Livingstone, 1995) the contents of which are inco ⁇ orated herein by reference.
  • the muscle relaxant is selected from the group consisting of guaifenesin, benzodiazepines (e.g., clozapine or diazopam), chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, other muscle relaxants having biphasic solubility, and combinations thereof. More preferably, the muscle relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, and combinations thereof.
  • a preferred muscle relaxant for use in the compositions of the invention is guaifenesin.
  • the muscle relaxant has biphasic solubility.
  • the muscle relaxant when present in the pharmaceutical composition, constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 20% by wt., and most preferably from about 5 % by wt. to about 15 % by wt.
  • Anti-Inflammatory Compounds when present in the pharmaceutical composition, constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 20% by wt., and most preferably from about 5 % by wt. to about 15 % by wt.
  • the transdermal compositions of the present invention may also include an anti-inflammatory compound.
  • an anti-inflammatory compound includes a compound which is capable of reducing cell migration, caused by ischemic and trauma associated events, and therefore reduces edema formation to thereby provide pain relief.
  • the anti-inflammatory compound is a nonsteroidal anti-inflammatory compound (i. e., NTHE) including ketoprofen.
  • NTHE nonsteroidal anti-inflammatory compound
  • Anti-inflammatory compounds, e.g., NTHEs are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al, eds., Merck & Co., Inc., Rahway, N.J., 1996, pp.
  • the NTHE is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, Vioxx ® , COX-2 NTHEs having biphasic solubility, and combinations thereof.
  • the NTHE is selected from the group consisting of celecoxib, etodolac, naproxen, COX-2 NTHEs having biphasic solubility, and combinations thereof.
  • the NTHE has biphasic solubility.
  • the NTHE, when present in the transdermal composition preferably, constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 30 % by wt., and most preferably from about 5 % by wt. to about 30 % by wt. Dosages
  • the concentration as well as the quantity of the amine containing compounds having biphasic solubility, the agents which enhance the activity of the amine containing compounds, e.g., the muscle relaxants, and the anti-inflammatory compounds can be varied independently in order to achieve the desired effect.
  • concentrations of the amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds contained in a dosage form of decreased viscosity may result in an analgesic with fast onset and short duration.
  • High concentrations of the amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds contained in a dosage form of increased viscosity may result in potent analgesic with fast onset and long duration.
  • Low concentrations of the amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds in a dosage form of decreased viscosity may result in mild analgesic with longer onset and short duration.
  • Low concentrations of the amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds contained in a dosage form of increased viscosity may have mild analgesic properties with longer onset and longer duration.
  • the ability to vary the concentration of the amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds from very low to high of the total composition, combined with the ability to coat thin (about 0.1 mm) or thick (about 0.5 mm) enables the practitioner of the invention to vary the dosage of the system as needed for particular level of pain and anatomical sites of interest. It should be appreciated, however, that onset time as well as duration of analgesic effect of the transdermal composition of the present invention will vary from subject to subject as well as on the basis of the site of application, and properties of the amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds.
  • the concentration of the amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds can range, on a weight basis, from about 1 % to about 30 % of the total composition, preferably from about 3 % to about 20 %, and more preferably from about 5 % to about 15 %.
  • the transdermal compositions of the present invention also includes a pharmaceutically acceptable carrier' which is capable of transdermal delivery of the amine containing compound having biphasic solubility.
  • a pharmaceutically acceptable carrier suitable for transdermal delivery includes a carrier capable of delivering the amine containing compound transdermally as defined above. Suitable carriers for transdermal delivery of pharmaceuticals are described in U.S. Patent No. 5,446,070, the contents of which are inco ⁇ orated herein by reference. Briefly, pharmaceutically acceptable carriers of the present invention include any suitable finite (i. e, solid) or non-finite ( .
  • non-solid such as liquid or semi-liquid carrier including liquids, semi-liquids or solid carriers, such as a bioadhesive.
  • a pharmaceutically acceptable carrier such as a cream, gel, emulsion, lotion, salve, paste, plaster, ointment, spray solution, or any other "non-finite" carrier known in the art of pharmaceutical delivery.
  • the base of a non-finite carrier may be lipid including phospholipids such as lecithins; fatty oils; lanolin; vasoline; paraffins; glycols; higher fatty acids; and higher alcohols.
  • bioadhesive as used herein includes an adhesive which attaches to a biological surface such as skin or mucosal tissue.
  • the bioadhesive of the present invention is self-adhesive in that it attaches to the site of interest without the need to reinforce its attachment by way of another adhesive.
  • Suitable bioadhesive include natural or synthetic polysaccharides such as cellulose derivatives including methylcellulose, cellulose acetate, carboxymethylcellulose, hydroxyethylcellulose and the like; pectin; a mixture of sulfated sucrose and aluminum hydroxide; hydrophilic polysaccharide gums including natural plant exudates, such as karaya gum, ghatti gum, tragacanth gum, xanthan gum, jaraya gum and the like; seed gums including guar gum, locust bean gum, psillium seed gum and the like; and lecithins such as soya lecithin.
  • compositions of the present invention may also include other ingredients such as various pharmaceutically acceptable additives available to those skilled in the art. These additives include binders, stabilizers, preservatives, flavorings, fragrances, and pigments.
  • the pharmaceutically acceptable carrier of the present invention includes van pen cream (cetyl alcohol, stearyl alcohol, steric acid, gllycerol monosterate, isopropyl myristate, soya lecithin, BHT alcohol 95%, simethicone, sodium hydroxide 30% solution, polyoxyl stearate, edetate disodium 5%, purified water, urea).
  • van pen cream cetyl alcohol, stearyl alcohol, steric acid, gllycerol monosterate, isopropyl myristate, soya lecithin, BHT alcohol 95%, simethicone, sodium hydroxide 30% solution, polyoxyl stearate, edetate disodium 5%, purified water, urea.
  • the invention features a transdermal composition suitable for transdermal delivery, which includes a therapeutically effective amount of a pharmaceutical compound (e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal delivery of the pharmaceutical compound.
  • a pharmaceutical compound e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence
  • a pharmaceutically acceptable carrier suitable for transdermal delivery of the pharmaceutical compound.
  • pharmaceutical compound includes compounds suitable for treating a targeted condition and capable of being delivered in active form, in
  • the pharmaceutical compound is a serotonin specific reuptake inhibitor (SSRI).
  • SSRIs are commonly prescribed for patients with diagnoses of mood disorders, some forms of anxiety disorder (particularly panic disorder), obsessive compulsive disorders, some forms of menopausal disorders, and eating disorders (especially bulimia nervosa).
  • Examples of such SSRIs include sertraline (sold under the trade name Zoloft), paroxetine (sold under the trade name Paxil), fluoxetine (sold under the trade name Prozac), venlafaxine (sold under the trade name Effexor), and fluvoxamine (sold under the trade name Luvox).
  • the pharmaceutical compound is a mood stabilizing medication, such as carbamazepine (sold under the trade name Tegretol) and valproic acid (sold under the trade name Depakote).
  • a mood stabilizing medication such as carbamazepine (sold under the trade name Tegretol) and valproic acid (sold under the trade name Depakote).
  • carbamazepine sold under the trade name Tegretol
  • valproic acid sold under the trade name Depakote
  • Mood stabilizing medications are also used in neurologic practice for the treatment of seizure disorders and for the treatment of certain pain disorders.
  • the pharmaceutical compound is a compound used for treating Attention Deficit Hyperactivity Disorder (ADHD), one example of which is permoline, sold under the trade name Cylert.
  • Permoline is a medication that is used in the treatment of Attention Deficit Hyperactivity Disorder in children and adults. It is practically insoluble in water, but soluble in ethylene glycol and lipids, making it a good candidate for transdermal administration.
  • the pharmaceutical compound is a dopamine compound, used for treating Parkinson's disease, examples of which are pergolide, sold under the trade name Permax and bromocriptine mesylate, sold under the trade name Parlodel.
  • the pharmaceutical compound is a compound used for treating hypertension and akathisia, one example of which is propranalol, sold under the trade name Inderal.
  • the pharmaceutical compound is a compound used in the treatment of impotence such as sildenafil, sold under the tradename Viagra. It is believed that transdermal administration of sildenafil may be useful, for at least some subjects, as compared to oral administration which has been found, in at least some situations, to be associated with gastrointestinal side effects.
  • Another embodiment of the present invention provides a method for preparing the above described transdermal compositions, by admixing a therapeutically effective amount of the amine containing compound having biphasic solubility, optimally an agent which enhances the activity of the amine containing compound, e.g., a muscle relaxant, optimally an anti-inflammatory compound with the carrier suitable for transdermal delivery of the amine containing compound.
  • a transdermal composition is prepared by dispersing or dissolving crushed tablets, capsules or other preparation(s) of the amine containing compound having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds, which were intended for oral delivery, in a gel formed of soya lecithin and isopropyl palmitate or isopropyl myristate, alcohol, or ethoxy diglycol.
  • Pluronic gel formed of Pluronic such as Pluronic F127, potassium sorbate and water is used.
  • a transdermal composition including a combination of doxepin with guaifenesin is useful for treating pain. It is believed that transdermal administration of such combination can be advantageous, for at least some patients, as compared to oral administration, because higher local pharmaceutical concentrations at the site(s), e.g., of injury, can be achieved yielding an improved therapeutic response without systemic side effects such as weight gain, drowsiness, gastrointestinal upset and/or other known side effects of these pharmaceuticals.
  • the invention feature methods for treating pain in a subject in which the subject is contacted with a transdermal composition including an amine containing compound having biphasic solubility in an amount effective to treat pain in the subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound to thereby treat pain in the subject.
  • the transdermal composition is applied to the skin of the subject as often as needed for the alleviation of pain.
  • the transdermal composition may be applied daily, weekly, monthly, yearly, for a length of time sufficient to alleviate pain.
  • Detailed examples of the preparation are provided below, along with examples of results obtained from transdermal administration to human patients.
  • a gel preparation is applied to the skin at the site or sites of pain.
  • Patients can be evaluated by means of a structured evaluation form, e.g., completed at a frequency of at least one time per week. Evaluation of patients are for the present symptoms as well as any side effects from currently administered medications. This makes it possible to note changes on an ongoing basis.
  • Compositions of the invention can be self-administered doses in the form of a gel applied to the skin by the patient, or be implemented by providing a transdermal preparation in premeasured doses preferably in connection with an adhesive or other covering or patch so that the dosage may be administered e.g., by placing the adhesive patch on the skin of the patient.
  • the location of the skin to which the pharmaceutical is applied is selected so as to relatively increase or decrease the delay, speed, duration, or rate of delivery of the pharmaceutical, either with respect to a particular tissue or systemically.
  • the transdermal formulation may be positioned adjacent the desired treatment area.
  • Membranes or matrices such as a polymer matrix, may be used to limit or control delivery rates.
  • delivery of the transdermal or aerosol formulation can be achieved, e.g. by administration as nose drops, eardrops, eyedrops and/or suppositories.
  • medications dispensed in transdermal gel form will be dispensed in unit doses, such as blister packs.
  • the gel will be extruded from the blister pack, and rubbed on the administration site.
  • the dosage will be adjusted by varying the number of unit dose applied. This will ensure accurate dosimetry and will avoid contamination of the gel.
  • the invention features a method for selecting a compound suitable for treating pain in a subject.
  • the method includes transdermally administering an amine containing compound having biphasic solubility to a subject; and determining whether pain is treated in the subject to thereby select a compound suitable for treating pain in a subject.
  • the method can further include modeling the compound using a computer equipped with a three-dimensional chemical structure modeling program (e.g., Molecules-3D Professional Edition, version 2.60, copyright 1991-1998, Molecular Arts Co ⁇ ., ⁇ 1994-1998 WCB/McGraw Hill); and determining whether the three-dimensional chemical structure of the compound possesses sufficient characteristics to be useful as a sodium or a calcium channel blocker, thereby selecting a compound suitable for treating pain in a subject.
  • a three-dimensional chemical structure modeling program e.g., Molecules-3D Professional Edition, version 2.60, copyright 1991-1998, Molecular Arts Co ⁇ ., ⁇ 1994-1998 WCB/McGraw Hill
  • the effectiveness of the amine containing compound having biphasic solubility to treat pain can be tested in vitro or in vivo.
  • An animal model for pain e.g., such as the one described in Krai M.G. et al (1999) Pain 81 (1 -2): 15-24 can, for example, be used for testing such compounds.
  • the transdermal compositions of the present invention include lamotrigine and doxepin; topiramate and chlorzoxazone; topiramate and guaifenesin; topiramate and doxepin; topiramate and naproxen; doxepin and chlorzoxazone; lamotrigine and guaifenesin; lamotrigine, doxepin, and guaifenesin; or lamotrigine, doxepin, and chlorzoxazone.
  • lecithin soya granular
  • 0.66 grams sorbic acid NF- FCC powder
  • isopropyl myristate NF isopropyl myristate NF and allowed to stand overnight.
  • a beaker was prepared by measuring to a volume of 100 milliliters. It was considered important to measure the volume accurately rather than using beaker markings.
  • An amount of Pluronic F127 NF (20 grams for a 20 percent gel, 30 grams for a 30 percent gel, 40 grams for a 40 percent gel) was mixed with 0.3 grams potassium sorbate NF. Refrigerated purified water was added in an amount sufficient to bring the volume to 100 milliliters. When all of the granules had been wet the gel was refrigerated. Solution took place upon cooling, taking 12 to 24 hours. The resulting 100 milliliters of Pluronic gel was kept refrigerated, since the gel will solidify at room temperature.
  • Example 4 Nine grams of carbamazepine in tablet form was ground in mortar and pestle. 4.3 milliliters of ethoxy diglycol was added and mixed to form a creamy paste. 13.2 milliliters of soya lecithin was added and mixed until smooth. The resulting 24 cc of solution was put into a 60 cc syringe. About 36 cc Pluronic F127 gel 20 percent (made according to Example 3) was placed in another syringe. The material was mixed well between syringes to yield 60 cc of carbamazepine organogel having a strength of 150 milligrams (mg) per milliliter. In some cases, the mixture was run through an ointment mill to reduce particle size.
  • Example 5 Sixty 100 milligram tablets of buproprion were ground and strained to form a fine powder. The buproprion powder was dissolved in 30 cc purified water, placed in a filter and washed with 10 to 20 cc purified water. The filtrate was used to make a 20 percent Pluronic gel using the procedures from Example 3, substituting filtrate for an equivalent volume of water, and stored in a refrigerator. Thirteen milliliters of soya lecithin was mixed with one-half the buproprion Pluronic gel and mixed between syringes to form a first batch. Thirteen milliliters of soya lecithin was mixed with the second half of the buproprion Pluronic gel and mixed between syringes to form a second batch. To each batch was added sufficient Pluronic gel F127 (made according to example 3) to yield a total of two 60 cc batches of buproprion HC1 organogel having a strength of 15 milligrams per milliliter.
  • 600 milligrams of fluoxetine HC1 (in the form of thirty 20 milligram capsules) was placed in a beaker and dissolved in approximately 18 cc of 95 percent ethyl alcohol. The solution was filtered through a filter funnel using fine filter paper. The residue was washed with 95 percent alcohol. The filtrate was heated, maintaining a temperature less than 85° C, to evaporate the alcohol to concentrate to 1 to 2 milliliters. 600 milligrams of isopropyl palmitate was combined with 600 milligrams of soya lecithin (granular), set aside and allowed to liquefy. Upon liquefaction, a thick syrupy consistency was obtained.
  • a Luer-oral adapter was attached to the mixture and transferred to six 1 milliliter oral syringes, was filled with 1 milliliter of the gel. In this way, each syringe contained five 20 milligram doses, or ten 10 milligram doses to yield a total of 60 doses of fluoxetine in lecithin organogel having a strength of 10 milligrams per 0.1 milliliters.
  • Example 7
  • F127 gel prepared according to Example 3, was added to achieve a volume of 60 cc and mixed well to yield 60 cc of nefazadone organogel having a strength of 50 milligrams per milliliter.
  • Venlafaxine hydrochloride has a solubility in water of 572 mg/mL (adjusted to ionic strength of 0.2 M with sodium chloride). Forty-five 100 milligram tablets of venlafaxine were crushed and put through a strainer. The powder was dissolved in 15 cc purified water, the solution placed into a filter and washed with 10 cc purified water. The filtrate was used to make a 20 percent Pluronic gel using the procedures of Example 3 (substituting the filtrate for an equivalent amount of water) and placed into a refrigerator overnight. 13.2 milliliters of soya lecithin were drawn into a syringe with a Luer loc.
  • the venlafaxine Pluronic gel was drawn into another syringe coupled to the first syringe and mixed well. Sufficient Pluronic F127 gel was added to achieve a volume of 60 cc with a strength of 75 mg. per cc.
  • Example 11 15 grams of sodium valproate (Depakote) was ground in mortar and pestle. 4 mL of ethoxy diglycol was added and mixed well to form a creamy paste. 19.8 mL of soya lecithin was added and mixed until smooth. The resulting 24 cc of solution was put into 2 syringes with a Luer Loc and mixed well. The mixture was divided so that half is in each syringe. Using another 60 cc syringe, Pluronic 30% gel was added to each to bring each syringe to a volume of 45 mL.
  • Pluronic 30% gel was added to each to bring each syringe to a volume of 45 mL.
  • Paroxetine hydrochloride has a solubility in water of 5.4 mg/mL.
  • Paroxetine (Paxil) gel was prepared, according to the procedures of example 8. A dosage of 40 mg per day was self-administered by a 59 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 210 days, blood was drawn and blood serum level of Paxil was determined to be 0 nanograms (ng) per mL, while typical reference levels are 49 ⁇ 26 ng/mL, indicating possible poor abso ⁇ tion or lab error. Clinical evaluation of the patient over a 210 day period of such transdermal administration indicated benefit to patient without GI side effects similar to that noted with oral preparation.
  • Sertraline hydrochloride is slightly soluble in water and isopropyl alcohol and sparingly soluble in ethanol.
  • Sertraline (Zoloft) gel was prepared, according to the procedures of example 9. A dosage of 100 mg per day was self-administered by a 54 year old female patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 19 days, blood was drawn and blood serum level of Zoloft was determined to be 5 ng/mL, while typical reference levels are 30-200 mg/mL indicating possible limited abso ⁇ tion or lab error.
  • Fluoxetine hydrochloride has a solubility in water of 14 mg/mL.
  • Fluoxetine (Prozac) gel was prepared, according to the procedures of example 6. A dosage of 20 mg per day was self-administered by a 54 year old female patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 7 days, blood was drawn and blood serum level of fluoxetine was determined to be 45 ng/ml, while the plasma level of the primary active metabolite norfluoxetin was also 45 ng/ml. There was evidence of patient benefit from the clinical evaluation.
  • Example 15 Carbamazepine is practically insoluble in water and soluble in alcohol and in acetone.
  • Carbamazepine (Tegretol) gel was prepared, according to the procedures of example 4. A dosage of 400 mg per day was self-administered by a 55 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 120 days, blood was drawn and blood serum level of Tegretol was determined to be 4.6 micrograms ( ⁇ g) per mL, while typical therapeutic levels are 4-10 ll ⁇ g/mL indicating good abso ⁇ tion. There were no GI side effects and the patient demonstrated clinical improvement.
  • Example 16 Carbamazepine (Tegretol) gel was prepared, according to the procedures of example 4. A dosage of 200 mg per day was self-administered by a 53 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 60 days, blood was drawn and blood serum level of Tegretol was determined to be 10.8 ⁇ g/mL, while typical therapeutic levels are 4-10 ll ⁇ g/mL indicating excellent abso ⁇ tion. There were no GI side effects and the patient demonstrated clinical improvement.
  • Sertraline (Zoloft) gel was prepared, according to the procedures of example 9.
  • a dosage of 50 mg per day was self-administered by a 53 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 63 days, blood was drawn and blood serum level of Zoloft was determined to be
  • Example 18 Carbamazepine (Tegretol) gel was prepared, according to the procedures of example 4. A dosage of 200 mg per day was self-administered by a 47 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 91 days, blood was drawn and blood serum level of Tegretol was determined to be less than 0.5 ⁇ g/mL, while typical therapeutic levels are 4-10 ⁇ g/mL, indicating poor abso ⁇ tion, lab error, or patient non-compliance.
  • Buproprion is highly soluble in water.
  • Buproprion (Wellbutrin) gel was prepared, according to the procedures of example 5. A dosage of 100 mg per day was selfadministered by a 47 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 44 days, blood was drawn and blood serum level of Wellbutrin was determined to be less than 0.5 ng/mL, while typical therapeutic levels are 10-30 indicating poor abso ⁇ tion, lab error, or patient non- compliance.
  • Example 20
  • Fluoxetine gel was prepared, according to the procedures of example 6..
  • a total daily adult dosage of fluoxetine as applied to the skin according to the present invention is between about 20mg and 200 mg, more preferably between about 120 mg and about 200 mg. Dosages for non-adults and/or non-human mammals may need to be adjusted, e.g. proportionally to body weight. A dosage of 20-60 mg per day was self-administered by 5 patients, including that of example 13 and also including a
  • Example 21 Fluoxetine gel was prepared, according to the procedures of example 6. A dosage of 80-160 mg per day was selfadministered by a 50 year old female by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 7 days at the 80 mg dosage level blood was drawn and the blood serum of fluoxetine was determined to be 34 ng/mL fluoxetine and 25 ng/mL norfluoxetine, while typical reference levels are 50-480 ng/mL, indicating good abso ⁇ tion. There was evidence of patient benefit from the clinical evaluation. The dosage was then increased to 160 mg per day and administered by the same method.
  • Example 22 Fluoxetine gel was prepared, according to the procedures of example 6. A dosage of 80-160 mg/day was self administered by a 38 year old female by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 7 days at the 80 mg dosage level, blood was drawn and the blood serum level of fluoxetine was determined to be 25 ng/mL of fluoxetine and 25 ng/mL norfluoxetine. There was evidence of patient benefit from the clinical evaluation. The dosage was then increased to 160 mg per day and administered by the same method.
  • Sertraline (Zoloft) gel was prepared, according to the procedures of example 9.
  • a dosage of 50-200 mg per day was self-administered by 6 patients, including those of examples 12 and 16 and also including a 60 year old male patient, a 53 year old male patient, a 48 year old male patient, a 38 year old male patient and a 47 year old male patient, by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation of the patients over a 7-90 day period of such transdermal administration indicated responses ranging from complete resolution of depression to no noticeable response.
  • Carbamazepine (Tegretol) gel was prepared, according to the procedures of example 4.
  • a dosage of 200-400 mg per day was self-administered by 6 patients, including those of examples 14, 15 and 17, and also including a 48 year old female patient, a 48 year old male patient and a 54 year old female patient, by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported.
  • Paroxetine (Paxil) gel was prepared, according to the procedures of example 8. A dosage of 20 mg per day was self-administered by the patient of example 12 as well as by a 15 year old female patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. Clinical evaluation of the patients over a 30-210 day period of such transdermal administration indicated equivocal clinical improvement of the depression which may (or may not) have been related to the transdermally administered Paxil.
  • Example 26 Five 150 mg tablets of amitriptyline were crushed and run through a strainer. The powder was put into syringes with a Luer Loc and mixed well with 2 mL ethoxy diglycol. About 6 mL Pluronic Gel 20% was added and mixed well. 6.6 mL Soya Lecithin was added and mixed well. This mixture was thinned to 30-mL total volume with Pluronic Gel 20% and mixed well. The resulting mixture having a strength of 25 mg/mL was placed in appropriate dispensing device.
  • Amitriptyline (Elavil) gel was prepared, according to the procedure of example 26. A dosage of 25 mg per day was self-administered by a 47 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation of the patients over a 100 day period of such transdermal administration indicated an apparently good clinical response, comparable to that achieved with oral medication.
  • Trazodone (Desyrel) gel was prepared, according to a procedure similar to that of example 7. A dosage of 50-150 mg per day was self-administered by 2 patients, including a 36 year old female patient and a 47 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation of the patients over a 42-90 day period of such transdermal administration indicated a good to excellent clinical response.
  • Venlafaxine (Effexor) gel was prepared, according to a procedure similar to that of example 9. A dosage of 150-225 mg per day was self-administered by 2 patients, including a 54 year old female patient and a 55 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation of the patients over a 15--
  • Propranolol (Inderal) gel was prepared, according to a procedure similar to that of example 8 to produce a gel having a strength of 40 mg of propranalol per mL of gel.
  • a dosage of 80 mg per day was self-administered by 2 patients, including a 36 year old female patient and a 47 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation of the patients over a 100 day period of such transdermal administration indicated results comparable to those achieved with oral medication.
  • Buproprion (Wellbutrin) gel was prepared, according to a procedure described in example 5.
  • a dosage of 150-200 mg per day was self-administered by 3 patients, including that of example 18, and also including a 38 year old male patient and a 53 year old female patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation of the patients over a 5-45 day period of such transdermal administration indicated equivocal results.
  • Example 32 Valproic acid (Depakote) gel was prepared, according to a procedure similar to that of example 4. A dosage of 1000 mg per day was self-administered by a 38 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation of the patients over a 30 day period of such transdermal administration indicated results comparable to those achieved with oral medication.
  • Example 33 Valproic acid (Depakote) gel was prepared, according to a procedure similar to that of example 4. A dosage of 1000 mg per day was self-administered by a 38 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation of the patients over a 30 day period of such transdermal administration indicated results comparable to those achieved with oral medication.
  • Example 33
  • Valproic acid (Depakote) gel was prepared according to the procedure of example 11. A dosage of 500-1000 mg was self administered by two male patients, ages
  • the 41 year old patient reported a good clinical response to an initial dosage of 250 mg administered twice daily, but a serum valproic acid level of only 1 ⁇ g/mL was obtained.
  • the dosage was increased to 500 mg twice daily, and a similar serum valproic acid level was obtained.
  • the disparity between the clinical response and the plasma level might be explained either by laboratory error or placebo effect.
  • Example 34 A gel containing reboxetine (sold under the trade name Edronax) is prepared according to a procedure similar to that described in example 5 but using reboxetine in place of boproprion. The resulting mixture will be self administered by patients by application to the skin for a period of at least I hour. No skin irritation or gastrointestinal side effects are expected. Clinical evaluation of patients over a 5-45 day period of such transdermal administration is expected to indicate a good response to treatment.
  • Nefazodone (Serzone) gel was prepared, according to a procedure described in example 7. A dosage of 100 mg per day was self-administered by a 61 year old (male, female) patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation of the patients over a 21 day period of such transdermal administration indicated a good response to treatment.
  • Example 36 1 gram of permoline tablets are crushed in a mortar and then dissolved in propylene glycol, just sufficient to effect dissolution. 3 mL of propylene glycol or 95% ethyl alcohol is added to form a paste. 6.6 mL soya lecithin is added to the mixture in the mortar. The mixture is placed in two syringes with a Luer Loc and mixed thoroughly. Each syringe is filled to 30 mL Pluronic F127 20% gel and mixed between syringes to produce a mixture having a strength of 33 mg/mL. The mixture is put in an appropriate dispensing device.
  • permoline prepared according to the procedure of example 36 will be administered transdermally, by application to the skin in the post auricular region for a period of at least one hour, at two sites, twice daily. No skin irritation is expected.
  • the clinical results are expected to be comparable to those obtained with the oral medication, although the dosage may have to be adjusted upwards to achieve adequate plasma levels, and more time may be required to achieve satisfactory plasma levels.
  • Valproic acid appears to cause skin irritation in some patients necessitating discontinuation. Both the laboratory measure of Buproprion and the patient clinical responses indicated poor or equivocal abso ⁇ tions and results.
  • Patient tolerance of transdermal administration has been good to excellent. Patients in the example above who suffered very severe GI side effects using oral preparations were more tolerant of the inconvenience of rubbing on the gel than were patients who had experienced only mild to moderate side effects. In general, more highly motivated and treatment-compliant patients also had a higher rate of sustained compliance. Patients in the examples above were evaluated by means of a structured evaluation form depicted in Fig. 1, which was completed at a frequency of at least one time per week for each patient receiving transdermal medication according to the present invention.
  • Example 38 1800 mg of gabapentin in powder form is dissolved with 1 mL propylene glycol in syringes with a Luer Loc. 6.6 mL of Soya lecithin is added and mixed thoroughly between syringes. The resulting material is placed in a device for dispensing measured amounts.
  • Gabapentin mixtures of 2% and 4% will be prepared by substituting 1200 mg gabapentin or 600 mg gabapentin in place of 1800 mg gabapentin, in example 38.
  • Example 40 Gabapentin, prepared according to Example 38 or 39, will be combined with either 3% or 5% Lidocaine in varying ratios.
  • Example 41 Gabapentin, prepared according to Example 38 or 39, will be combined with either 3% or 5% Lidocaine in varying ratios.
  • 2% gabapentin, prepared according to Example 38 or 39, will be combined with 2% carbamazepine and 1 % Piroxicam, which is expected to yield better penetration into muscle tissue.
  • Gabapentin prepared according to Example 38 or 39, in concentrations ranging from 2%-6% will be combined with clonidine in concentrations between .2% and .3%.
  • Example 44 A 56-year-old woman had painful upper and lower extremity spasms as a result of spastic quadriparesis resulting from an injury. Oral gabapentin, an anticonvulsant, had been administered previously, but had caused a "drugged" feeling, one of the commonly reported side effects with this agent. It was believed that use of transdermal gabapentin might provide local relief by achieving high local tissue concentrations near the site of administration without correspondingly elevated blood plasma levels. It is known that other anticonvulsants, such as carbamazepine, are useful in reducing neurogenic pain. Gabapentin's solubility in water exceeds 10%, making systemic abso ⁇ tion less likely. Gabapentin prepared according to the procedure of example 38 was self-administered by application to the skin in the area of pain. The patient reported moderate relief of spasms over a period of one week, with no systemic side effects and no report of skin irritation.
  • Example 46 6 grams of doxepin was added to 20 milliliters Pluronic 33% F 127 and put into a refrigerator to dissolve. 24 grams of ketoprofen and 12 grams of guaifenesin was added to 10 milliliters of 95% alcohol and mixed well. 26.4 milliliters of soya lecithin was added and mixed well and the doxepin composition was mixed with the ketoprofen guaifenesin composition. The resulting mixture was added to sufficient Pluronic 33% to yield 120 milliliters. The resulting composition was mixed well to yield a composition having about 20% ketoprofen, 5% doxepin and 10% guaifenesin.
  • doxepin 6 grams was added to 26 milliliters Pluronic 33% and refrigerated to dissolve. 2 milliliters ethoxy diglycol was added 4.8 grams carbamazepine and mixed. The resultant mixture was added to 24 grams ketoprofen and six milliliters alcohol and the result was mixed well. 26.4 milliliters soya lecithin was added to the ketoprofen composition and mixed well. The doxepin composition was mixed with the carbamazepine/ ketoprofen composition and sufficient Pluronic 33% was added to yield 120 milliliters. The resultant composition was mixed well to yield a composition having about 20% ketoprofen, 4% carbamazepine and 5% doxepin.
  • compositions according the examples 45 through 47, 53, 55 were transdermally applied to numerous patients, for the pu ⁇ ose of treating pain including as described in other examples herein, with the results summarized in Table I below.
  • Table II The meaning of certain entries in Table I is indicated in Table II below. Blank results indicate no treatment at the pertinent site for this patient. Where a given line of Table I shows more than one site, one "best" (greatest pain relief) result if shown in bold.
  • Example 53 24 grams ketoprofen and sufficient guaifenesin to result in a 10% final guaifenesin concentration, was mixed well with 10 milliliters 95% alcohol. 1200 mg gabapentin was dissolved in one ml propylene glycol in a syringe with a luer loc. 26.4 ml of soya lecithin was added to the ketoprofen-guaifenesin-alcohol mixture and mixed well. The resulting mixture was added to the gabapentin-propylene glycol mixture and mixed well. 4.8 gm of carbamazepine was combined with the resultant combination and mixed well to form a smooth paste. The resulting paste was combined with the ketoprofen-guaifenesin-alcoholgabapentin mixture and mixed well with sufficient pluronic to yield 120 ml of a composition containing ketoprofen 20%, carbamazepine
  • doxepin powder Six grams of doxepin powder combined with 26 milliliters pluronic and placed in the refrigerator until dissolved. 1200 mg gabapentin was mixed with 1 ml propylene glycol and placed in a syringe with luer lock. 6.6 ml of soya lecithin was added and mixed well between syringes. 24 gm of ketoprofen and 8 milliliters alcohol was mixed well between two syringes with luer loc. The doxepin mixture was mixed well with the gabapentin mixture and subsequently the ketoprofen mixture was added and mixed well. Sufficient pluronic 20% (about 54 ml) was added to yield 60 ml of a composition having about 20% ketoprofen, 4% weight percent gabapentin and 5% weight percent doxepin.
  • a 57 year old female applied a mixture, prepared generally according to example 55, containing ketoprofen 20%, gabapentin 4%, and doxepin 5% for a period of 8 weeks to her neck and reported major relief. She applied the same mixture to her shoulder and reported moderate relief. A mixture that substituted piroxicam for the doxepin produced only mild shoulder relief.
  • Example 57 A 35 year old man with a history of knee injury with vascular compromise and 3 surgeries applied a mixture, prepared generally according to example 45, containing 4% carbamazepine and 5% amitriptyline to his knee, and reported mild to moderate pain relief, without skin irritation nor other side effects.
  • Example 61 A 38 year old man with a history of shoulder strain applied a mixture, prepared generally according to example 45, containing 4% carbamazepine and 5% amitriptyline to his shoulder for a period of 2 weeks. He reported mild to moderate pain relief, and reported no skin irritation nor other side effects.
  • Example 61 A 38 year old man with a history of shoulder strain applied a mixture, prepared generally according to example 45, containing 4% carbamazepine and 5% amitriptyline to his shoulder for a period of 2 weeks. He reported mild to moderate pain relief, and reported no skin irritation nor other side effects.
  • Example 61 A 38 year old man with a history of shoulder strain applied a mixture, prepared generally according to example 45, containing 4% carbamazepine and 5% amitriptyline to his shoulder for a period of 2 weeks. He reported mild to moderate pain relief, and reported no skin irritation nor other side effects.
  • Example 61 A 38 year old man with a history of shoulder strain applied a mixture, prepared generally according
  • Example 65 12 g doxepin was mixed with 50 ml Pluronic F 127 33% and placed in a refrigerator to dissolve. 12 g gabapentin was dissolved in 9 ml ethoxy diglycol and mixed to form a smooth paste. 52.8 ml of soya lecithin was added and mixed well. The doxepin/Pluronic mixture was added and mixed well. Sufficient quantity of Pluronic F
  • a 36 year old man with a knee injury involving joint surface damage and vascular comprise applied a mixture, prepared generally according to Example 65 to his knee several times per day. He reported moderate to major (40%) relief of pain that persisted for 4 to 6 hours. An earlier trial of carbamazepine-amitriptyline gel produced no relief when applied to his knee.
  • 6 gm doxepin was mixed with 18 ml of Pluronic 33% to and placed in a refrigerator to dissolve.
  • 6 gm gabapentin was ground in a mortar and pestle to a fine powder, added to 6 ml ethoxy diglycol and mixed to form a smooth paste.
  • 12 gm guaifenesin was added and mixed well.
  • 26.4 ml soya lecithin was added and mixed well.
  • the doxepin/Pluronic mixture was added and mixed well.
  • Pluronic gel Sufficient quantity of Pluronic gel (25.2 ml of 33% Pluronic, although 30% or 20% Pluronic can be used), was added to produce 120 ml of a composition having about 5 wt% gabapentin, about 5 wt% doxepin and about 10 wt% guaifenesin.
  • a 59 year old woman with cervical and back strain applied a mixture, prepared generally according to example 51, but without steps involving ketoprofen) containing about 5 wt % doxepin and about 10 wt% guaifenesin, to her neck for a period of two weeks, two to four times per day, and achieved total relief. She applied the same mixture to her back and achieved major to total relief.
  • doxepin HCI 4.5 gm was dissolved using 2.5 ml 95% alcohol and mixed well between syringes. It is also possible to mix the doxepin with 5 ml Pluronic 20%) and place in a refrigerator to dissolve. Sufficient quantity of 20% Pluronic F127 was added to produce 90 ml of a composition having about 5 wt% doxepin. Preferably this and other disclosed compositions are protected from light.
  • a formulation of 7% antidepressant and about 10%) muscle relaxant was prepared by dissolving 3.15 g of trimipramine and 4.5 g of guaifenesin in a mixer jar using 2.7 mL of ethoxy diglycol. About 9.9 mL of soya lecithin was added and the mixture was mixed well. Sufficient quantity of Pluronic F127 NF (20%) to make total volume of about 45 mL was added and mixed well.
  • a gel formulation of 30% NTHE was prepared from 36 g of celecoxib, 7.2 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (20%) to make total volume of 120 mL.
  • a gel formulation containing about 7% antidepressant and about 13%) muscle relaxant was prepared from 14.4 g of doxepin, 31.2 g of guaifenesin, 12 mL of ethoxy diglycol, 52.8 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 240 mL.
  • a gel formulation containing 5% antiepileptic was prepared from 6 g of lamotrigine, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F 127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% adrenergic agonist was prepared from 12 g of crushed tizanidine, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% muscle relaxant was prepared from 12 g of crushed metaxalone, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% muscle relaxant was prepared from 12 g of crushed carisoprodol, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% methocarbamol was prepared from 12 g of crushed methocarbamol, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% muscle relaxant was prepared from 12 g of crushed dantrolene sodium, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%>) to make total volume of 120 mL.
  • Example 81
  • a gel formulation containing 7% antidepressant, 10% muscle relaxant was prepared from 8.4 g of crushed doxepin, 12 g of chlorzoxazone, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • doxepin appears to be an effective pain relief medication when administered transdermally and appears to be substantially free of side effects when administered transdermally as described herein.
  • Doxepin appears to provide about three times the positive response rate compared to at least some other pharmaceutical agents described herein, regardless of whether such other pharmaceutical agents are administered singly or in combination. Doxepin appears to be substantially more effective than amitriptyline as a pain, e.g., neuropathic pain agent when administered transdermally. This appears to be true regardless of whether doxepin is administered as a single agent or is administered in combination with other pharmaceuticals as described herein.
  • Carbamazepine appears to provide positive effects as a pain, e.g., neuropathic pain agent, at least in properly selected patients. Carbamazepine appears to cause a rash in at least some patients, requiring its discontinuation.
  • Gabapentin appears to be free of side effects when administered transdermally. Although some patients appear to derive some benefit from a combination of transdermally administered ketoprofen, gabapentin, and prioxicam. the effect appears to be relatively weak compared to the effect provided by doxepin. Guaifenesin appears to provide benefit as an adjunctive treatment, of painful spasticity. For the patient population described herein, amitriptyline appeared to offer limited pain relief when administered transdermally. It appears that combining gabapentin with doxepin may offer some additional benefit. The addition of guaifenesin to doxepin may be of particular value when painful spasticity is present.
  • the invention provides treatment to patients for whom oral delivery is suboptimal, such as patients who experience gastrointestinal or other side effects, patients who experience poor absorption for orally delivered pharmaceuticals and/or patients who benefit from delivery over an extended period or a relatively rapid delivery or higher rate of increase of plasma levels.
  • the present invention achieves delivery of therapeutic amounts of pharmaceuticals, for at least some patient populations, substantially without skin irritation, gastrointestinal or other side effects associated with orally-delivered pharmaceuticals, especially psychopharmaceuticals, and yields clinical benefits comparable to or greater than those received by patients to whom corresponding pharmaceuticals were administered orally.
  • particularly effective pain medications are those described in examples 65, 67, 69 and
  • blood plasma levels may be increased by providing for two or more transdermal applications per day and/or applying a transdermal composition to two or more sites.
  • Zyprexa or a fluoxetine/olanzapine mixture in a lecithin organogel will prove useful.
  • psychostimulant medications for which the described transdermal delivery may be used including psychostimulant medications.
  • One example of a psychostimulant medication is Methylphenidate (sold under the trade name Ritalin) used in the treatment of attention deficit hyperactivity disorder (ADHD).
  • ADHD attention deficit hyperactivity disorder
  • Methylphenidate typically has a 2-4 hour duration of action necessitating frequent dosing of a patient which is particularly difficult to accomplish with children in school.
  • transdermal administration it will be possible to achieve an extension of effective dosing throughout the day, eliminating the need for frequent oral medication administration. It is believed that transdermal administration will also eliminate peaks and valleys of blood plasma levels which, it is believed, will be more clinically effective. It is believed similar results will be obtained with other pharmaceuticals, for example, Dextroamphetamine (under the trade name Dexedrine) although it is believed the need is less acute since a time release "spansule" form of the medication is available which typically has a 5-6 hour duration of action.
  • Another group of psychotropic medications which, it is believed, will benefit from transdermal delivery includes antipsychotic medication such as those used in the treatment in schizophrenia.
  • Embodiments of the invention include, but are not necessarily limited to, use by patients with enteric absorption deficits.

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Abstract

L'invention concerne des méthodes et des compositions d'administration transdermiques. Dans un premier mode de réalisation, l'invention concerne des méthodes et des compositions d'administration transdermiques d'un composé aminé à solubilité biphasique et/ou d'un agent qui stimule l'activité du composé aminé à solubilité biphasique, par exemple, un myorelaxant, pour soulager la douleur.
PCT/US2002/000019 2001-01-03 2002-01-03 Methodes et compositions transdermiques pour le soulagement de la douleur WO2002053187A2 (fr)

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AU2002234192A8 (en) 2008-03-13
US20010029257A1 (en) 2001-10-11
US6572880B2 (en) 2003-06-03
WO2002053187A3 (fr) 2008-01-17

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